Change in newly diagnosed Graves' disease phenotype between the twentieth and the twenty-first centuries: meta-analysis and meta-regression.

PURPOSE: According to a few recent studies, the clinical phenotype of Graves' disease (GD) at onset is becoming milder in recent years, in terms of prevalence and severity of hyperthyroidism, goiter and overt eye disease. The aim of this study was to assess the change in GD phenotype across the late twentieth and the early twenty-first centuries. MATERIALS AND METHODS: We carried out a systematic search of studies published between 1/1/1980 and 12/31/2017 describing naïve GD patients at diagnosis. We collected epidemiological, clinical, biochemical and serological data reported in the selected studies, and (1) conducted a single-arm meta-analysis to compare clinical and biochemical characteristics of naïve GD patients before and after year 2000 and (2) performed a meta-regression to identify the trend of the observed clinical presentations. RESULTS: Eighty selected articles were related to the period before the year 2000, 30 to the years 2000-2017. According to demographics, the two defined populations were homogeneous at meta-analysis: overall estimated female prevalence was 81% [95% CI 79-82], mean estimated age of the entire population was 39.8 years [95% CI 38.4-41.1], with no significant differences between pre- and post-2000 groups (p > 0.05). The overall estimated prevalence of smokers was 40% [95% CI 33-46], with no significant difference between the two groups (p > 0.05). Mean estimated free thyroxine (FT4) and free triiodothyronine (FT3) levels at diagnosis were higher in the pre-2000 group: 4.7 ng/dl [95% CI 4.5-4.9] for FT4 and 14.2 pg/ml [95% CI 13.3-15.1] for FT3, as compared to the post-2000 group: 3.9 ng/dl [95% CI 3.6-4.2] for FT4 and 12.1 pg/ml [95% CI 11.0-13.3] for FT3 (all p < 0.01). Goiter estimated prevalence was higher in the pre-2000 group, 87% [95% CI 84-90], than in the post-2000 group, 56% [95% CI 45-67]. Estimated prevalence for Graves' Orbitopathy (GO) was 34% [95% CI 27-41] in the pre-2000 group and 25% [95% CI 19-30] in the post-2000 group (p = 0.03). Accordingly, meta-regression adjusted for covariates showed an average annual reduction of FT4 (- 0.040 ± 0.008 ng/dl, p < 0.0001), FT3 (- 0.316 ± 0.019 pg/ml, p < 0.0001), goiter prevalence (- 0.023 ± 0.008%, p = 0.006), and goiter size (- 0.560 ± 0.031 ml, p < 0.0001). CONCLUSIONS: Our meta-analysis and meta-regression confirmed that GD phenotype at diagnosis is nowadays milder than in the past; we hypothesize that conceivable factors involved in this change are iodoprophylaxis, worldwide decrease in smoking habits, larger use of contraceptive pill and micronutrient supplementation, as well as earlier diagnosis and management.

Features and outcome of differentiated thyroid carcinoma associated with Graves' disease: results of a large, retrospective, multicenter study.

BACKGROUND: Whether differentiated thyroid cancer (DTC) occurring concomitantly with Graves' disease (GD) is more aggressive and bound to a less favorable outcome is controversial. OBJECTIVE: Aim of this multicenter retrospective study was to compare baseline features and outcome of DTC patients with GD (DTC/GD+) or without GD (DTC/GD-). PATIENTS: Enrolled in this study were 579 patients referred to five endocrine units (Cagliari, Pavia, Pisa, Siena, and Varese) between 2005 and 2014: 193 patients had DTC/GD+ , 386 DTC/GD-. Patients were matched for age, gender and tumor size. They underwent surgery because of malignancy, large goiter size, or relapse of hyperthyroidism in GD. RESULTS: Baseline DTC features (histology, lymph node metastases, extrathyroidal extension) did not differ in the two groups, except for multifocality which was significantly more frequent in DTC/GD+ (27.5% vs. 7.5%, p < 0.0001). At the end of follow-up (median 7.5 years), 86% of DTC/GD+ and 89.6% DTC/GD- patients were free of disease. Patients with persistent or recurrent disease (PRD) had "biochemical disease" in the majority of cases. Microcarcinomas were more frequent in the DTC/GD+ group (60% vs. 37%, p < 0.0001) and had an excellent outcome, with no difference in PRD between groups. However, in carcinomas ≥ 1 cm, PRD was significantly more common in DTC/GD+ (24.4% vs. 11.5%; p = 0.005). In the whole group, univariate and multivariate analyses showed that GD+ , lymph node involvement, extrathyroidal invasion, multifocality and tall cell histotype were associated with a worse outcome. Female gender and microcarcinomas were favorable features. No association was found between baseline TSH-receptor antibody levels and outcome. Graves' orbitopathy (GO) seemed to be associated with a better outcome of DTC, possibly because patients with GO may early undergo surgery for hyperthyroidism. CONCLUSIONS: GD may be associated with a worse outcome of coexisting DTC only if cancer is ≥ 1 cm, whereas clinical outcome of microcarcinomas is not related to the presence/absence of GD.

Malignant cutaneous tumours of the scalp: always remember to examine the head.

Around 2% of cutaneous neoplasms arise in the scalp (scalp tumours: STs). They can be classified as primary STs (epithelial, melanocytic and adnexal) or metastatic (from distal tumours or as a spreading from contiguous structures). This anatomic location is usually poorly examined during dermatological consultations, also due to the presence of the hair cover. Moreover, self-examination of the hair-covered skin is often harder for the patient. The peculiar features of the scalp may explain the worse prognosis of STs compared with neoplasms of other locations. The hair coverage protects the scalp from UV radiations, but due to the complex pathogenesis of STs, they may also develop in younger patients. Until now, STs have been not extensively investigated in the dermatological literature, and most publications are written by otolaryngologists, or by head, neck and plastic surgeons. Thus, dermatologists above all have the opportunity and the task to explore the scalp carefully, with the opportunity to make an early diagnosis, possibly changing the patient's prognosis. The aim of this paper was to review the main STs in order to increase awareness among dermatology specialists.

Antithyroid drug treatment for Graves' disease: baseline predictive models of relapse after treatment for a patient-tailored management.

BACKGROUND: Antithyroid drugs (ATDs) are first-line treatment for Graves' hyperthyroidism worldwide, but relapses are frequent. The reliability of individual risk factors to predict at baseline subsequent relapse is poor. Predictive scores grouping single risk factors might help to select the best treatment (pharmacological vs. ablative). OBJECTIVE: To assess the predictivity of a recently developed score (Clinical Severity Score, CSS) and to compare it with another score (GREAT score). PATIENTS: A retrospective observational, single-center study was conducted of 387 consecutive, newly diagnosed Graves' patients, who completed an 18-24 months ATD course and were followed for at least 2 years. RESULTS: Hyperthyroidism relapsed in 185 patients (48%). At diagnosis and before treatment, the relapse group had higher serum TSH-receptor antibody and free thyroxine levels and larger goiters than the remission group, with no differences in Graves' orbitopathy prevalence and severity. In the multivariate analyses, only large goiter size was significantly associated with an increased recurrence hazard ratio. Using CSS, the risk of relapse increased from 36% in the mild category and 49% in the moderate category to 59% in the severe category, with quite a good area under the curve (AUC) (0.60; 95% CI: 0.55; 0.66). GREAT score showed an increase in relapse from 34% for class I (mild) and 49% for class II (moderate) to 64% for class III (severe) (AUC, 0.63; CI: 0.58; 0.68). CONCLUSIONS: Both CSS and GREAT score are useful, although imperfect, tools to predict at baseline relapse of hyperthyroidism after treatment. In real life they may help the clinician to tailor a treatment for newly diagnosed Graves' hyperthyroidism.

Imaging technique for the diagnosis of onychomatricoma.

Onychomatricoma is a rare tumour that derives from the nail matrix and grows within the nail plate. The clinical presentation can mimic many other tumours and conditions, and surgical biopsy and histopathological examination are necessary to confirm the diagnosis. As nail surgery is a painful experience for the patient and sometimes can leave permanent onychodistrophy, more precise preoperative diagnosis is needed to distinguish onychomatricoma from other nail diseases more accurately and to limit surgical interventions. The objective of this study was to evaluate current literature on imaging techniques for the diagnosis of onychomatricoma in order to understand how this technology can help the presurgical diagnosis of this tumour. We searched in the Cochrane Skin Group Specialised library, Medline, Embase and LILACS databases all studies evaluating imaging technique for the diagnosis of onychomatricoma up to February 2018. We found that not only nail dermoscopy, but also reflectance confocal microscopy, optical coherence tomography, ultrasonography and magnetic resonance can be useful in this field.

Physical performance in newly diagnosed hypothyroidism: a pilot study.

OBJECTIVE: Hypothyroidism is complicated by neuromuscular symptoms (myalgias, slowness of movements, and tiredness) and signs (easy fatigability and cramps), which may have a negative impact on general well-being and quality of life. In a pilot, prospective, controlled study, we investigated the features of muscle dysfunction in hypothyroidism by disease questionnaire, biochemical measures, and physical performance tests. MATERIALS AND METHODS: Fifty-seven consecutive patients with newly diagnosed hypothyroidism were enrolled, 27 subclinical (S-Hypo) and 30 overt (O-Hypo). A series of 30 euthyroid subjects, with similar demographic characteristics, served as controls. Patients were administered a short disease questionnaire and underwent laboratory exams and standardized physical tests, both at baseline and after restoration of biochemical euthyroidism. RESULTS: Compared to euthyroid controls, the O-Hypo group showed significantly higher prevalence of neuromuscular symptoms and significantly higher serum creatine phosphokinase (CPK) levels (p value < 0.0001). S-Hypo had slightly higher CPK levels and prevalence of neuromuscular symptoms than controls. Both S-Hypo and O-Hypo patients performed worse than controls in the six-minute walking test. Differences between patients and controls in handgrip strength test and timed chair standing test failed to reach statistical significance (although a trend was noticeable), possibly due to the small sample size. In O-Hypo, an inverse correlation was found between CPK levels and the handgrip strength test (p value < 0.001). Restoration of euthyroidism was associated with normalization of questionnaire responses, six-minute walking test, as well as serum CPK levels. CONCLUSION: In addition to neuromuscular symptoms, hypothyroidism is associated with abnormalities of physical performance. The six-minute walking test is the most valuable test to assess this aspect. In the pilot study, levothyroxine therapy could reverse muscle functional abnormalities.

Does early response to intravenous glucocorticoids predict the final outcome in patients with moderate-to-severe and active Graves' orbitopathy?

PURPOSE: Intravenous glucocorticoids (ivGCs) given as 12-weekly infusions are the first-line treatment for moderate-to-severe and active Graves' orbitopathy (GO), but they are not always effective. In this study, we evaluated whether response at 6 weeks correlated with outcomes at 12 (end of intervention) and 24 (follow-up) weeks, particularly in patients initially unresponsive. METHODS: Our database (Bartalena et al. J Clin Endocrinol Metab 97:4454-4463, 10), comprising 159 patients given three different cumulative doses of methylprednisolone (2.25, 4.98, 7.47 g) was analyzed, pooling data for analyses. Responses at 6 weeks were compared with those at 12 and 24 weeks using three outcomes: overall ophthalmic involvement [composite index (CI)]; quality of life (QoL); Clinical Activity Score (CAS). Responses were classified as "Improved", "Unchanged", "Deteriorated", compared to baseline. RESULTS: Deteriorated patients at 6 weeks for CI (n = 8) remained in the same category at 12 weeks and 7/8 at 24 weeks. Improved patients at 6 weeks for CI (n = 51) remained in the same category in 63% and 53% of cases at 12 and 24 weeks, respectively. Unchanged patients at 6 weeks (n = 100) eventually improved in 28% of cases (CI), 58% (CAS), 32% (QoL). There was no glucocorticoid dose-dependent difference in the influence of early response on later outcomes. CONCLUSIONS: Patients who deteriorate at 6 weeks after ivGCs are unlikely to benefit from continuing ivGCs. Patients unresponsive at 6 weeks still have a significant possibility of improvement later. Accordingly, they may continue ivGC treatment, or, alternatively, possibly stop ivGCs and be switched to a second-line treatment.

Prevalence of abdominal aortic aneurysms and its relation with cardiovascular risk stratification: protocol of the Risk of Cardiovascular diseases and abdominal aortic Aneurysm in Varese (RoCAV) population based study.

BACKGROUND: Recent meta-analyses suggested that screening program for abdominal aortic aneurysms (AAA) in 65-year old males is cost-effective at prevalence of about 1%. Since some events occur also in females and among the youngers, screening could be feasible among those at higher risk, such as smokers or individuals with a family history of AAA. The RoCAV (Risk of Cardiovascular diseases and abdominal aortic Aneurysms in Varese) Project is a population-based study aimed to evaluate AAA prevalence in Northern Italy in males over-65 years as well as among females and younger males, and to identify new markers for risk stratification by collecting a large set of CVD risk factors. The aims of the project are: (i) cross-sectional evaluation of AAA prevalence (ii); evaluation of standard CVD risk score as criteria for selecting subgroup at higher risk to be included in a screening program; (iii) identification of new risk markers and risk score algorithm for AAA and CVD risk stratification; (iv) cost-effective evaluation during the follow-up. METHODS: Males aged 50-75 years and females aged 60-75 years, resident in the city of Varese (Lombardy Region), were randomly selected from the civil registry. Among 5198 successfully invited, 3777 subjects accepted to participate and were finally recruited (participation rate 63.8%) from June 2013 to May 2016. Trained operators administered a computerized anamnestic questionnaire, measured anthropometric parameters (BMI, body circumferences, skinfolds), blood pressure, ankle-brachial index, pulse wave velocity and performed abdominal aortic ultrasound scan, ECG and spirometry. All methods were internationally validated. A blood sample was collected and stored in biobank. A follow-up will be carried out through linkage with electronic records. DISCUSSION: Participation rate and data quality assessment were as expected and will reasonably allow to reach the project aims. The expected impact in public health of the RoCAV project will be the potential implementation of a AAA screening program to the whole region as well as the formulation of new criteria for risk assessment of AAA and CVD.

Masked hypertension in newly diagnosed hypothyroidism: a pilot study.

PURPOSE: Masked hypertension (MH) is the association of normal office blood pressure (BP) with high ambulatory or home BP. This condition is associated with increased cardiovascular target organ damage, as true hypertension. Because the relation with hypothyroidism is controversial, we investigated it in a pilot longitudinal and controlled study. METHODS: We consecutively enrolled 64 newly diagnosed hypothyroid patients, 38 subclinical (s-HYPO), and 26 overt (o-HYPO). The control group consisted of 50 euthyroid subjects seen at outpatient clinics. All participants underwent office and 24-h ambulatory BP measurement. RESULTS: BP monitoring revealed a higher prevalence of MH both in s-HYPO (26.3 %) and in o-HYPO (15.4 %) than in euthyroid subjects (10 %, p = 0.05); true hypertension also was more frequent in o-HYPO (11.5 %) and s-HYPO (10.5 %) than in controls (8 %, p = 0.03). The odds ratio for hypertension versus normotension confirmed a significantly increased risk of MH in hypothyroid patients versus euthyroid subjects (3.29, 1.08-10.08; p = 0.02). In a subgroup of patients reevaluated after restoration of euthyroidism, an improvement of BP profile was observed, especially in s-HYPO subgroup, with a decreased prevalence of MH (from 25 to 10.7 %) and true hypertension (from 10.7 to 3.4 %). CONCLUSIONS: Hypothyroidism may be an important predictor of higher BP values, with an increased risk of MH. Because MH is a cardiovascular risk and can be reversed by thyroid hormone replacement, its presence should represent an indication for thyroid hormone replacement therapy also in patients with s-HYPO.

The phenotype of newly diagnosed Graves' disease in Italy in recent years is milder than in the past: results of a large observational longitudinal study.

OBJECTIVE: The Merseburg triad (hyperthyroidism, goiter, and orbitopathy) characterizes classical description of Graves' disease (GD). Aim of this observational, longitudinal study was to evaluate the current clinical features of newly diagnosed GD in Italy. MATERIALS AND METHODS: In two Northern Italy centers (Varese and Pavia), 283 consecutive patients (211 women, 72 men; mean age 47.4 years) with newly diagnosed GD were recruited in the years 2010-2014. Diagnosis was based on established criteria, and thyroid volume was assessed by ultrasonography. A clinical severity score (CSS) to assess the overall disease severity was developed by grading each component of the Merseburg triad. RESULTS: At diagnosis, 45 % of patients had no goiter, and 30 % had a small goiter. The proportion of goitrous patients was much lower than in two Italian studies performed 20-30 years ago. Hyperthyroidism was subclinical in 16 % and mild in 29 % of patients, and Graves' orbitopathy was present in 20 %, usually mild, and active in only 2.5 % of patients. Using the CSS, less than half (44 %) of the patients had severe GD, while 22 % had mild and 34 % moderate disease. CSS was associated with a significantly higher risk of poorly controlled hyperthyroidism at 6 months. CONCLUSIONS: In Italy, a relevant proportion of Graves' patients at diagnosis have mild to moderate GD; about half of them have no goiter, slightly less than one-fifth have subclinical hyperthyroidism, and only 20 % have GO. Thus, the clinical phenotype of GD is milder than in the past, possibly due to both earlier diagnosis and treatment, and improved iodine nutrition.

Clinical leadership and hospital performance: assessing the evidence base.

BACKGROUND: A widespread assumption across health systems suggests that greater clinicians' involvement in governance and management roles would have wider benefits for the efficiency and effectiveness of healthcare organisations. However, despite growing interest around the topic, it is still poorly understood how managers with a clinical background might specifically affect healthcare performance outcomes. The purpose of this review is, therefore, to map out and critically appraise quantitatively-oriented studies investigating this phenomenon within the acute hospital sector. METHODS: The review has focused on scientific papers published in English in international journals and conference proceedings. The articles have been extracted through a Boolean search strategy from ISI Web of Science citation and search source. No time constraints were imposed. A manual search by keywords and citation tracking was also conducted concentrating on highly ranked public sector governance and management journals. Nineteen papers were identified as a match for the research criteria and, subsequently, were classified on the basis of six items. Finally, a thematic mapping has been carried out leading to identify three main research sub-streams on the basis of the types of performance outcomes investigated. RESULTS AND CONTRIBUTION: The analysis of the extant literature has revealed that research focusing on clinicians' involvement in leadership positions has explored its implications for the management of financial resources, the quality of care offered and the social performance of service providers. In general terms, the findings show a positive impact of clinical leadership on different types of outcome measures, with only a handful of studies highlighting a negative impact on financial and social performance. Therefore, this review lends support to the prevalent move across health systems towards increasing the presence of clinicians in leadership positions in healthcare organisations. Furthermore, we present an explanatory model summarising the reasons offered in the reviewed studies to justify the findings and provide suggestions for future research.

Long-term effects of inhaled budesonide on screening-detected lung nodules.

BACKGROUND: A previously carried out randomized phase IIb, placebo-controlled trial of 1 year of inhaled budesonide, which was nested in a lung cancer screening study, showed that non-solid and partially solid lung nodules detected by low-dose computed tomography (LDCT), and not immediately suspicious for lung cancer, tended to regress. Because some of these nodules may be slow-growing adenocarcinoma precursors, we evaluated long-term outcomes (after stopping the 1-year intervention) by annual LDCT. PATIENTS AND METHODS: We analyzed the evolution of target and non-target trial nodules detected by LDCT in the budesonide and placebo arms up to 5 years after randomization. The numbers and characteristics of lung cancers diagnosed during follow-up were also analyzed. RESULTS: The mean maximum diameter of non-solid nodules reduced significantly (from 5.03 mm at baseline to 2.61 mm after 5 years) in the budesonide arm; there was no significant size change in the placebo arm. The mean diameter of partially solid lesions also decreased significantly, but only by 0.69 mm. The size of solid nodules did not change. Neither the number of new lesions nor the number of lung cancers differed in the two arms. CONCLUSIONS: Inhaled budesonide given for 1 year significantly decreased the size of non-solid nodules detected by screening LDCT after 5 years. This is of potential importance since some of these nodules may progress slowly to adenocarcinoma. However, further studies are required to assess clinical implications. CLINICAL TRIAL NUMBER: NCT01540552.

Workplace drug testing on urine samples: evidence for improving efficacy of a first-level screening programme.

BACKGROUND: Previous reports revealed poor performance in identifying drugs of abuse users through first-level workplace drug testing (WDT), based on urine samples. In a cross-sectional study, we evaluated: (i) the effect of creatinine normalization of drug values from diluted urine samples (creatinine levels ≤ 20 mg/dL) on the prevalence of drug users; (ii) the independent procedure-related predictors of positivity and dilution. METHODS: Workers' urine samples were collected at the workplace or at our certified laboratory between 2008 and 2012. All samples were analysed for drugs of abuse by immuno-enzymatic method in our laboratory, according to the Italian WDT law. Detectable drugs of abuse concentrations lower than the positive cutoff values were normalized based on mean levels of urinary creatinine. Detectable concentrations of drugs were confirmed by GC/MS. Multivariate logistic regression was used to detect independent procedure-related predictors of positive and diluted urine samples. RESULTS: Of the 3080 urine samples screened, 51 (1.7%) were found positive for some drugs of abuse (26 cannabinoids and 16 cocaine) and 116 (3.8%) were diluted. Seventeen out of 23 diluted urine samples with detectable concentrations of cannabinoids or cocaine were found positive after urine creatinine normalization and GC/MS confirmed both negative and positive results. This increased the percentage of positivity for cannabinoids and cocaine from 1.35% to 2.09% (+55%, p=0.0005), which is closer to the expected prevalence of drug users based on Italian self-reported surveys. Collection of samples in the laboratory was an independent predictor of positivity (OR=2.33, 95%CI 1.27-4.28) and diluted urine sample (OR=1.65, 95%CI 1.04-2.61). CONCLUSIONS: Efficacy of first-level WDT could be improved by well-controlled pre-analytical procedures and urine creatinine normalization of detected concentrations of drugs of abuse.

Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology.

Non-small-cell lung cancer (NSCLC) is a very common disease in the elderly population and its incidence in this particular population is expected to increase further, because of the ageing of the Western population. Despite this, limited data are available for the treatment of these patients and, therefore, the development of evidence-based treatment recommendations is challenging. In 2010, European Organization for Research and Treatment of Cancer (EORTC) took an initiative in collaboration with International Society of Geriatric Oncology (SIOG) and created an experts panel that provided an experts' opinion consensus paper for the management of elderly NSCLC patients. Since this publication, important new data are available and EORTC and SIOG recommended to update the 2010 recommendations. Besides recommendations for surgery, adjuvant chemotherapy and radiotherapy, treatment of locally advanced and metastatic disease, recommendations were expanded, to include data on patient preferences and geriatric assessment.

2nd ESMO Consensus Conference on Lung Cancer: early-stage non-small-cell lung cancer consensus on diagnosis, treatment and follow-up.

To complement the existing treatment guidelines for all tumour types, ESMO organises consensus conferences to focus on specific issues in each type of tumour. The 2nd ESMO Consensus Conference on Lung Cancer was held on 11-12 May 2013 in Lugano. A total of 35 experts met to address several questions on non-small-cell lung cancer (NSCLC) in each of four areas: pathology and molecular biomarkers, first-line/second and further lines in advanced disease, early-stage disease and locally advanced disease. For each question, recommendations were made including reference to the grade of recommendation and level of evidence. This consensus paper focuses on early-stage disease.